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A20 deficiency in lung epithelial cells protects against influenza A virus infection

Jonathan Maelfait (UGent) , Kenny Roose (UGent) , Lars Vereecke (UGent) , Conor Mc Guire (UGent) , Mozes Sze (UGent) , Martijn Schuijs (UGent) , Monique Willart (UGent) , Lorena Ibanez (UGent) , Hamida Hammad (UGent) , Bart Lambrecht (UGent) , et al.
(2016) PLOS PATHOGENS. 12(1).
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Abstract
A20 negatively regulates multiple inflammatory signalling pathways. We here addressed the role of A20 in club cells (also known as Clara cells) of the bronchial epithelium in their response to influenza A virus infection. Club cells provide a niche for influenza virus replication, but little is known about the functions of these cells in antiviral immunity. Using airway epithelial cell-specific A20 knockout (A20(AEC-KO)) mice, we show that A20 in club cells critically controls innate immune responses upon TNF or double stranded RNA stimulation. Surprisingly, A20(AEC-KO) mice are better protected against influenza A virus challenge than their wild type littermates. This phenotype is not due to decreased viral replication. Instead host innate and adaptive immune responses and lung damage are reduced in A20(AEC-KO) mice. These attenuated responses correlate with a dampened cytotoxic T cell (CTL) response at later stages during infection, indicating that A20(AEC-KO) mice are better equipped to tolerate Influenza A virus infection. Expression of the chemokine CCL2 (also named MCP-1) is particularly suppressed in the lungs of A20(AEC-KO) mice during later stages of infection. When A20(AEC-KO) mice were treated with recombinant CCL2 the protective effect was abrogated demonstrating the crucial contribution of this chemokine to the protection of A20(AEC-KO) mice to Influenza A virus infection. Taken together, we propose a mechanism of action by which A20 expression in club cells controls inflammation and antiviral CTL responses in response to influenza virus infection.
Keywords
DISEASE TOLERANCE, CLARA CELLS, IMMUNE-PATHOLOGY, EFFECTOR T-CELLS, NF-KAPPA-B, CHEMOATTRACTANT PROTEIN-1 GENE, SINGLE-STRANDED RNA, TOLL-LIKE RECEPTOR-3, ANTIVIRAL RESPONSES, DENDRITIC CELLS

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Citation

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Chicago
Maelfait, Jonathan, Kenny Roose, Lars Vereecke, Conor Mc Guire, Mozes Sze, Martijn Schuijs, Monique Willart, et al. 2016. “A20 Deficiency in Lung Epithelial Cells Protects Against Influenza A Virus Infection.” Plos Pathogens 12 (1).
APA
Maelfait, J., Roose, K., Vereecke, L., Mc Guire, C., Sze, M., Schuijs, M., Willart, M., et al. (2016). A20 deficiency in lung epithelial cells protects against influenza A virus infection. PLOS PATHOGENS, 12(1).
Vancouver
1.
Maelfait J, Roose K, Vereecke L, Mc Guire C, Sze M, Schuijs M, et al. A20 deficiency in lung epithelial cells protects against influenza A virus infection. PLOS PATHOGENS. 2016;12(1).
MLA
Maelfait, Jonathan, Kenny Roose, Lars Vereecke, et al. “A20 Deficiency in Lung Epithelial Cells Protects Against Influenza A Virus Infection.” PLOS PATHOGENS 12.1 (2016): n. pag. Print.
@article{7103148,
  abstract     = {A20 negatively regulates multiple inflammatory signalling pathways. We here addressed the role of A20 in club cells (also known as Clara cells) of the bronchial epithelium in their response to influenza A virus infection. Club cells provide a niche for influenza virus replication, but little is known about the functions of these cells in antiviral immunity. Using airway epithelial cell-specific A20 knockout (A20(AEC-KO)) mice, we show that A20 in club cells critically controls innate immune responses upon TNF or double stranded RNA stimulation. Surprisingly, A20(AEC-KO) mice are better protected against influenza A virus challenge than their wild type littermates. This phenotype is not due to decreased viral replication. Instead host innate and adaptive immune responses and lung damage are reduced in A20(AEC-KO) mice. These attenuated responses correlate with a dampened cytotoxic T cell (CTL) response at later stages during infection, indicating that A20(AEC-KO) mice are better equipped to tolerate Influenza A virus infection. Expression of the chemokine CCL2 (also named MCP-1) is particularly suppressed in the lungs of A20(AEC-KO) mice during later stages of infection. When A20(AEC-KO) mice were treated with recombinant CCL2 the protective effect was abrogated demonstrating the crucial contribution of this chemokine to the protection of A20(AEC-KO) mice to Influenza A virus infection. Taken together, we propose a mechanism of action by which A20 expression in club cells controls inflammation and antiviral CTL responses in response to influenza virus infection.},
  articleno    = {e1005410},
  author       = {Maelfait, Jonathan and Roose, Kenny and Vereecke, Lars and Mc Guire, Conor and Sze, Mozes and Schuijs, Martijn and Willart, Monique and Ibanez, Lorena and Hammad, Hamida and Lambrecht, Bart and Beyaert, Rudi and Saelens, Xavier and van Loo, Geert},
  issn         = {1553-7366},
  journal      = {PLOS PATHOGENS},
  language     = {eng},
  number       = {1},
  pages        = {17},
  title        = {A20 deficiency in lung epithelial cells protects against influenza A virus infection},
  url          = {http://dx.doi.org/10.1371/journal.ppat.1005410},
  volume       = {12},
  year         = {2016},
}

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